Re-engineering therapeutic antibodies for Alzheimer’s disease as blood-brain barrier penetrating bi-specific antibodies

ABSTRACT

Introduction: Therapeutic antibodies are large molecule drugs that do not cross the blood-brain barrier (BBB). Therefore, drug development of therapeutic antibodies for Alzheimer’s disease (AD) requires that these molecules be re-engineered to enable BBB delivery. This is possible by joining the therapeutic antibody with a transporter antibody, resulting in the engineering of a BBB-penetrating bispecific antibody (BSA).

Areas covered: The manuscript covers transporter antibodies that cross the BBB via receptor-mediated transport systems on the BBB, such as the insulin receptor or transferrin receptor. Furthermore, it highlights therapeutic antibodies for AD that target the Abeta amyloid peptide, beta secretase-1, or the metabotropic glutamate receptor-1. BSAs are comprised of both the transporter antibody and the therapeutic antibody, as well as IgG constant region, which can induce immune tolerance or trigger transport via Fc receptors.

Expert opinion: Multiple types of BSA molecular designs have been used to engineer BBB-penetrating BSAs, which differ in valency and spatial orientation of the transporter and therapeutic domains of the BSA. The plasma pharmacokinetics and dosing regimens of BSAs differ from that of conventional therapeutic antibodies. BBB-penetrating BSAs may be engineered in the future as new treatments of AD, as well as other neural disorders.

KEYWORDS:

• Blood-brain barrier
• bispecific antibody
• brain drug delivery
• Alzheimer’s disease
• CSF

Article highlights

• Therapeutic antibodies are large molecule drugs that do not cross the blood-brain barrier (BBB).

• Therapeutic antibodies can be re-engineered for BBB transport by combination with a transporter antibody and the engineering of a BBB-penetrating bispecific antibody (BSA).

• The transporter antibody targets a receptor-mediated transport system on the BBB, such as the insulin receptor or transferrin receptor.

• Design considerations in the engineering of the BSA are the valency of the therapeutic and transporter antibody domains, as well as the spatial separation of the antibody domains of the BSA.

• A BBB-penetrating BSA for Alzheimer’s disease (AD) was formed by re-engineering an anti-Abeta peptide antibody as a single chain Fv (ScFv) antibody, and fusion of the ScFv to the carboxyl terminus of the heavy chain of a transporter antibody targeting either the human insulin receptor, for delivery in monkeys and humans, or the mouse transferrin receptor, for drug delivery in AD mice.

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Declaration of interest

W Pardridge is a consultant for ArmaGen Inc. He has no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

Additional information

Funding

This manuscript has not been funded.